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Antimicrobial Agents and Chemotherapy, May 2000, p. 1236-1241, Vol. 44, No. 5
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Inhibition of Human Rhinovirus-Induced Cytokine
Production by AG7088, a Human Rhinovirus 3C Protease
Inhibitor
L. S.
Zalman,*
M. A.
Brothers,
P. S.
Dragovich,
R.
Zhou,
T. J.
Prins,
S. T.
Worland, and
A. K.
Patick
Agouron Pharmaceuticals, Inc., San Diego,
California 92121
Received 6 August 1999/Returned for modification 18 October
1999/Accepted 7 February 2000
Symptom severity in patients with human rhinovirus (HRV)-induced
respiratory illness is associated with elevated levels of the
inflammatory cytokines interleukin-6 (IL-6) and IL-8. AG7088 is a
novel, irreversible inhibitor of the HRV 3C protease. In this study,
AG7088 was tested for its antiviral activity and ability to inhibit the
production of IL-6 and IL-8 in a human bronchial epithelial cell line,
BEAS-2B. Infection of BEAS-2B cells with HRV 14 resulted in the
production of both infectious virus and the cytokines IL-6 and IL-8.
Treatment of HRV 14-infected cells with AG7088 resulted in a
statistically significant (P, <0.05) dose-dependent
reduction in the levels of infectious virus as well as IL-6 and IL-8
released into the cell supernatant compared to the results obtained for
compound-free infected cells. AG7088 was also able to inhibit the
replication of HRV 2 and 16 in BEAS-2B cells. In time-of-addition
studies, AG7088 could be added as late as 14 to 26 h after HRV 14 infection of BEAS-2B cells and still result in a statistically
significant (P, <0.05) reduction in the levels of
infectious virus, IL-6, and IL-8 compared to the results obtained for
compound-free infected cells. These findings have implications for the
development of an antirhinovirus agent that may not only block virus
replication but also diminish symptoms.
*
Corresponding author. Mailing address: Department of
Virology, Agouron Pharmaceuticals, Inc., 4245 Sorrento Valley Blvd., San Diego, CA 92121. Phone: (619) 622-3062. Fax: (619) 622-5999. E-mail: zalman{at}agouron.com.
Antimicrobial Agents and Chemotherapy, May 2000, p. 1236-1241, Vol. 44, No. 5
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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